The work described in this grant application will bring about fundamental knowledge in two important areas of current aging research. The first is calorie restriction (CR), which is a dietary regimen known to provide broad health benefits and longevity. The second is SIR2 and its related proteins (sirtuins), which have emerged in the past five years as important regulators of aging in a broad spectrum of model organisms. Studies in the prior period have begun to identify pathways by which CR operates in C. elegans. The first two aims in this grant will focus in on these pathway and identify hormones and cellular processes that are critical for CR to extend the lifespan of worms. We have pinpointed two neurons in the head that trigger broad physiological changes in response to CR, such as an increase in respiration, and we will figure out what hormonal factor these cells release to bring about the observed changes leading to long lifespan. In the third aim, we will study in detail the four sirtuin genes in C. elegans. Since sirtuins have been linked to CR in other organisms, we will investigate whether this is true in worms, which sirtuins are involved, and how they bring about their effects. The C. elegans system we have set up to study CR offers many advantages, including all of the genetic and molecular tools that have solved many other important biological problems in the nematode model. CR itself has salutary effects against many of the major diseases of aging in rodent models. It is possible that a molecular understanding of CR will allow us to tap genetic pathways to provide broad health benefits for our aging population. This approach is complementary to the current focus on the molecular details of particular diseases to develop specific therapies. Beyond this important practical outcome, this study will provide important new information on the sirtuins and pathways that relate diet to physiology. There is an excellent foundation to build on in the next granting period and important findings are anticipated. Public Health relevance: Dietary restriction is the most robust intervention that extends life span and improves health in mammals. This project details a study of dietary restriction in the roundworm C. elegans that will identify new genes, mechanisms and pathways driving this process. Our findings may lead to new therapeutic approaches to diseases of aging in humans.